#315 Hypomagnesemia-induced proximal tubular injury and nephrocalcinosis in rats: insights into FHHNC pathophysiology

Abstract Background and Aims Patients with hypomagnesemia experience a more rapid decline in renal function compared to those with normomagnesemia [1]. Inflammation and oxidative stress are implicated in the pathophysiology of hypomagnesemia-associated kidney injury [2], though the underlying mechanisms remain unclear. In humans, mutations in Claudin-16 and Claudin-19 genes result in chronic hypomagnesemia due to increased urinary magnesium excretion. This condition, mediated through bone resorption triggered by elevated parathyroid hormone (PTH), leads to progressive renal dysfunction with nephrocalcinosis, a hallmark of Familial Hypomagnesemia, Hypercalciuria, and Nephrocalcinosis (FHHNC) [3]. However, while Claudin-16 knockout mice exhibit hypomagnesemia without nephrocalcinosis or kidney injury, and Claudin-19 knockout mice have shown no reported renal injury [4], the exact mechanisms remain poorly understood. Previous studies in rats have demonstrated that a magnesium-deficient diet can induce renal tubular injury with calcification [5]. In this study, we investigated renal injury in a rat model of hypomagnesemia induced by a low-magnesium diet in greater detail. Method Rats were fed a low-magnesium diet, and renal injury was evaluated histologically. Serum magnesium and other electrolytes, as well as PTH levels, were measured. Results Histological analysis of kidney tissue revealed dilated tubules in the corticomedullary region. These dilated tubules were negative for the proximal tubule marker megalin but positive for the dedifferentiation marker vimentin and the proximal tubule injury marker Kim-1, indicating proximal tubule injury. Additionally, calcium deposition was observed in these tubules, as evidenced by positive von Kossa staining. Serum analysis revealed hypomagnesemia, hypophosphatemia, and elevated PTH levels. Magnesium sulfate supplementation improved both serum electrolyte abnormalities and histological changes (Fig. 1). Conclusion The rat model of hypomagnesemia-induced proximal tubular injury with calcification demonstrated pathological and serological findings similar to FHHNC. This model may provide valuable insights and opportunities for developing novel treatments for FHHNC.